Trifluoromethyl-substituted alcohols of Formula (I) have been described as ligands that bind to the glucocorticoid receptor.

These compounds are effective as therapeutics in treating a number of diseases modulated by glucocorticoid receptor function, including inflammatory, autoimmune and allergic disorders. Examples of these compounds are described in U.S. Patent Application Publication Nos. 2003/0232823 and 2004/0029932, and U.S. Pat. No. 6,903,215, which are each incorporated herein by reference in their entireties and are hereinafter termed “the Trifluoromethyl-Substituted Alcohol Patent Applications”.
It is well known in the art that enantiomers of a particular compound can have different biological properties including efficacy, toxicity, and pharmacokinetic properties. Thus, it is often desirable to administer one enantiomer of a racemic therapeutic compound.
The synthetic methods disclosed in the patent applications cited above describe the synthesis of racemic products. Separation of enantiomers was accomplished by chiral HPLC and may be accomplished by other conventional ways of separating enantiomers. Chiral HPLC and other enantiomer separation method, however, are generally unsuitable for large-scale preparation of a single enantiomer. Thus, a stereoselective synthesis for preparation of these compounds would be highly desirable.
The present invention discloses an efficient stereoselective synthesis of certain compounds of Formula (I). A key step involves an efficient chiral resolution of a beta-hydroxy acid and a one-step synthesis of a 6-azaindole subunit. The novel one-step azaindole synthesis from an ester has been previously described in our U.S. Ser. No. 11/070,462, which is incorporated by reference. This new synthesis has fewer steps and utilizes relatively inexpensive starting materials, therefore providing a more economical synthesis of the drug substance.